1. Field of the Invention
The invention relates to inhibitors of aldosterone biosynthesis and compositions and methods for treating hyperaldosteronism.
2. Description of the Prior Art
Primary aldosteronism is the constellation of chemical and clinical abnormalities resulting from the autonomous hypersecretion of the mineralocorticoid aldosterone, as opposed to secondary aldosteronism which refers to hypersecretion of aldosterone in response to a known stimulus such as angiotensin.
Primary aldosteronism is most frequently caused by an aldosterone-secreting adenoma (Conn's syndrome), but it is sometimes associated with adrenal hyperplasia or can be idiopathic in origin.
Hypersecretion of aldosterone, whether primary or secondary, leads to excessive conservation of sodium, causing elevation of blood pressure, suppression of renin production and expansion of extracellular volume. Aldosterone hypersecretion also causes excessive excretion of potassium which may result in, inter alia, hypokalemic alkalosis, muscular weakness, electrocardiographic abnormalities, and impaired renal concentrating capacity. The principal clinical manifestations of primary aldosteronism are hypertension and its sequelae.
The treatment of choice in primary aldosteronism is surgical excision of the adenomatous adrenal gland. However, patients who are poor surgical risks, those who are unwilling to undergo adrenal exploration, and those whose hyperaldosteronism persists after surgery are conventionally treated with an aldosterone antagonist such as spironolactone. Spironolactone promotes natriuresis and inhibits potassium excretion by acting as a competitive antagonist of aldosterone in the cortical collecting duct of the renal tubule. Spironolactone is also commonly administered for several weeks prior to surgery to patients undergoing excision of adrenal adenomas.
While relatively effective in antagonizing the pernicious effects of hyperaldosteronism, spironolactone has marked antiandrogenic side effects, including decreased libido, impotence and gynecomastia in males, and menstrual irregularities in females. These side effects limit the long-term usefulness of the drug, particularly in males. Other untoward effects of spironolactone include diarrhea, rash and urologic disturbances, as well as the development of hyperkalemia in certain patients.
While other potassium-sparing agents (e.g., triamterene and amiloride) have been used to treat the hypertension caused by hyperaldosteronism, such agents are normally not potent when used alone because only a small volume of tubular fluid reaches their distal sites of action in the cortical collecting ducts.
Improved agents for treating hyperaldosteronism and its sequelae are currently being sought.